Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization

Abstract

Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in human peripheral blood and shown to be incorporated into foci of neovascularization, consistent with postnatal vasculogenesis. We determined whether endogenous stimuli (tissue ischemia) and exogenous cytokine therapy (granulocyte macrophage-colony stimulating factor, GM-CSF) mobilize EPCs and thereby contribute to neovascularization of ischemic tissues. The development of regional ischemia in both mice and rabbits increased the frequency of circulating EPCs. In mice, the effect of ischemia-induced EPC mobilization was demonstrated by enhanced ocular neovascularization after cornea micropocket surgery in mice with hindlimb ischemia compared with that in non-ischemic control mice. In rabbits with hindlimb ischemia, circulating EPCs were further augmented after pretreatment with GM-CSF, with a corresponding improvement in hindlimb neovascularization. There was direct evidence that EPCs that contributed to enhanced corneal neovascularization were specifically mobilized from the bone marrow in response to ischemia and GM-CSF in mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. These findings indicate that circulating EPCs are mobilized endogenously in response to tissue ischemia or exogenously by cytokine therapy and thereby augment neovascularization of ischemic tissues.

Endothelial progenitor cells: Implications for cardiovascular disease

“…Stem cells within the bone marrow usually exist in a quiescent state and specific signals stimulate the stem cells to differentiate and to be mobilized into the systemic circulation. Beside humoral factors such as cytokines (51)(52)(53), hormones (51,53,54), chemokines (37,55), and drugs (56-58), exercise training (ET) has been shown to increase the number of circulating EPCs (8,9,59,60).…”

Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis

“…In humans, CECs have been detected in diverse conditions having in common endothelial damage, such as coronary angioplasty, acute coronary syndrome, sickle cell anemia, thrombotic thrombocytopenic purpura, infection with Rickettsia conorii or cytomegalovirus, Behçet's disease, systemic lupus erythematosus (SLE), and small-vessel vasculitis (7)(8)(9)(10)(11)(12)(13)(14)(15). Moreover, it has been suggested that in response to severe ischemia or cytokine stimuli, circulating endothelial cell progenitors (CEPs) increase and home into sites of angiogenesis and/or vascular damage, and consequently contribute to neovascularization and/or wound-healing processes (16)(17)(18).…”

Impaired Vascular Remodeling after Endothelial Progenitor Cell Transplantation in MMP9-Deficient Mice Suffering Cortical Cerebral Ischemia

“…EPCs can be mobilized in response to ischemia, can home to sites of neovascularization, and can differentiate into endothelial cells. 1 There are two subsets of EPCs: the so-called circulating angiogenic cells and the outgrowth endothelial cells (OECs). 2 Both types of EPCs have been demonstrated to increase brain angiogenesis in animal models of cerebral ischemia.…”